The primary objective is to develop efficient technology for synthesis of kilogram amounts of oligonucleotides and other potential anticancer compounds. A secondary goal is to apply the technology to the development of small-molecule combinatorial libraries for anticancer and anti-AIDS drug screening. Specific research aims are: (1) completing development and construction of the automated synthesis instrument designed in Phase 1; (2) selecting a high-load, high-efficiency solid-support matrix and optimizing synthetic chemistry; (3) integrating automated in situ synthon formation/activation and DNA synthesis; (4) achieving reproducible 98-99% stepwise synthesis efficiency at the 10-100g scale; (5) developing process-scale isolation and purification protocols; (6) synthesizing 10-100g amounts of several potential anticancer agents of pharmaceutical- grade; (7) performing in vitro biological testing for efficacy and toxicity, and for comparison to compounds produced by current methods; (8) demonstrating significant efficiency improvement and cost-reduction compared to current methods; (9) applying the system to the synthesis of small-molecule (<700 MW) combinatorial library mixtures containing components at concentrations greater than 100muM; and (10) performing chemical analysis of the library mixtures to confirm their suitability for cell-based and in vitro drug screening applications. More efficient and economical technology for scale-up synthesis of oligonucleotides, anticancer agents and combinatorial libraries will facilitate the identification and evaluation of new therapeutic agents. PROPOSED COMMERCIAL APPLICATION: The project will develop scale-up technology for synthesizing antisense oligonucleotides and other compounds in kilogram amounts for use in the development, clinical trials and manufacture of new pharmaceutical products with anticancer and anti- AIDS applications. The extension of the technology to the development of combinatorial libraries will accelerate the identification of new potential pharmaceutical agents by enabling very large numbers of different materials to be produced efficiently and cost-effectively for biological activity screening programs.